Coronary atherosclerosis, a leading cause of death in Western countries, is strongly influenced by genetic factors. Identification of the specific genes and sequence variants that confer susceptibility to atherosclerosis has been hampered by two major obstacles: 1)the pathogenesis of atherosclerosis is extremely complex, and 2) the human genome is highly polymorphic, containing an estimated 10 million DNA sequence variants. Since most polymorphisms probably have little effect on gene function, this enormous heterogeneity has confounded efforts to identify sequence variants that systematically influence disease phenotypes. To identify sequence variants associated with coronary atherosclerosis we performed a genome-wide association study and validated 50 of the associations observed by replication in independent samples of cases and controls. In this grant we will address two critical questions: 1) Which of these 50 SNPs are reproducibly associated with coronary atherosclerosis, and 2) What is the mechanism by which these SNPs confer genetic susceptibility to coronary atherosclerosis. These questions will be addressed in three sequential steps. First, we will validate the associations observed by replication in a third, independent population, the Atherosclerosis Risk in Communities (ARIC) study. Second, we will fine map the genomic regions confirmed to be associated with coronary atherosclerosis, and screen genes in the associated interval for functional SNPs. Third, to elucidate the mechanisms underlying the associations observed we will test for association between the SNPs identified and cardiovascular risk factors (e.g. plasma lipid and lipoprotein levels, blood pressure, C-reactive protein) in the Dallas Heart Study, a large, multiethnic, population-based study in which detailed phenotyping of cardiovascular risk factors has been performed. Our preliminary data provide compelling evidence to support this approach: two of the loci we have identified are strongly associated with coronary heart disease in multiple independent case-control comparisons from different populations assayed by two different methods. One of these loci identifies a novel gene that is associated with associated with direct measures of coronary atherosclerosis but not with intermediate phenotypes such as blood cholesterol or blood pressure. The second locus encodes the proprotein convertase PCSK9 which is associated with decreased levels of LDL-C and substantial protection against incident CHD in the ARIC cohort and against prevalent CHD in the cohort from Ottawa. Relevance: The identification of SNPs associated with atherosclerosis may provide a molecular handle on novel pathways that influence susceptibility to atherosclerosis, and reveal new therapeutic targets for prevention and treatment of CHD.